The present invention relates to the storage and dispensing of substances. More particularly, the invention provides a system, and method of use, for serially dispensing a large number of reagents into a plurality of receptacles.
In chemical and biological laboratories, reagent transfer from a source vessel to a target receptacle is a fundamental task. Typically, a technician must retrieve various reagent bottles from a storage location, each containing a substance pertinent to the task at hand. The technician then manually pipettes a precise quantity of each into an appropriate reaction receptacle, such as a selected well of a multi-well plate. To prevent contamination, the pipette tip must be cleaned after contact with each different reagent, or it must be discarded and replaced with a new tip.
Alternatively, the technician can attempt to manually pour each of the collected reagents from its storage vessel into a desired reaction receptacle. However, given the ultra-small quantities of reagents typically called for in modern-day protocols, particularly for expensive reagents, this technique can be very tedious and difficult to accurately perform. Moreover, the act of pouring often leads to wasted reagent, e.g., where excessive amounts are inadvertently dispensed, and cross-contamination between receptacles can result, especially when working in a high-density receptacle format (e.g., a plate or tray having ninety-six wells).
Thus, it is not surprising that such manual techniques fail to meet the demands of most laboratories, where very small quantities of numerous (e.g., hundreds or thousands) reagents must be dispensed in a quick and accurate manner.
While systems are known that automate certain aspects of reagent storage, retrieval and/or dispensing, these too are associated with certain disadvantages. One such system, available from Sagian Inc. (Indianapolis, Ind.), automates the picking and placing of reagents. Briefly, to xe2x80x9cpickxe2x80x9d a reagent is to retrieve it from a reagent file, and to xe2x80x9cplacexe2x80x9d it is to re-file it back into the reagent file. The Sagian system employs two industrial robots to move reagents to and from an operator area. The first robot is a mini-trieve that moves to a vertical file holding a target reagent and then pulls out an appropriate drawer containing the reagent. The robot then delivers the drawer to another work area where a CRS articulated robot removes the requested reagent, verifies that it is the correct container by passing the container in front of a bar-code scanner, and places it into one of a series of racks which are accessible by the operator. The mini-trieve then returns the drawer to its original location in the file. While eliminating much of the labor burden and handling errors generally associated with manual techniques, manual intervention is nevertheless required in order to dispense the reagent. Moreover, much wasted effort is involved since each drawer retrieved by the robot usually contains hundreds of additional reagents that do not pertain to the task at hand. Further, the robotic motions involved, and distances traversed, in retrieving each reagent can be quite substantial. Cumulatively, the overall process can be quite time consuming, particularly in situations where a great number of reagents (e.g., hundreds or thousands) must be retrieved.
Another automated system is sold under the trade name HAYSTACK, available from The Automation Partnership Group pIc (Melbourn Science Park, Melbourn, Royston, Hertfordshire, UK). Similar to the Sagian system, the HAYSTACK system utilizes industrial robots to retrieve drawers of reagents from vertical files. In addition to such pick-and-place functions, The Automation Partnership offers modules that are able to carry out various dispensing steps. Such added capability, however, substantially increases the operational complexity of the system, and can consume a great deal of valuable laboratory space, as well.
There is, thus, a need for a relatively simple and compact reagent storage and dispensing system that provides for variable (custom) retrieval, as well as quick and accurate dispensing, of numerous selected reagents.
In one of its aspects, the present invention provides a system for storing and dispensing a plurality of reagents.
According to one embodiment, the system includes an addressable array of reagent dispensers, each having a gate mechanism disposed at a lower outlet region thereof. The gate mechanisms are independently operable between (i) an opened condition permitting passage of a respective reagent through the outlet region, and (ii) a closed condition whereat such passage is blocked. A first support is disposed below the dispenser array, and a second support, having a holding area for receiving a plurality of receptacles, is mounted on the first support. The first and second supports can be, for example, independently operable xy stages. The first support is variably positionable in a manner permitting placement of a fixed target region thereof directly under any selected one of the dispensers in the array. The second support is variably positionable in a fashion permitting placement of any selected target site of the receptacle-holding area directly over the fixed target region.
Each of the dispensers can be, for example, an elongated container having a longitudinally extending passageway configured to receive and hold a respective reagent when the gate mechanism is in the closed condition.
A rack having an array of holding cells can support the containers. According to one embodiment, the rack has at least 100 holding cells, and preferably in excess of 1,000 holding cells. Exemplary racks include, for example, 5,000, 10,000, 50,000, 100,000 and 500,000 holding cells. Each holding cell can be configured to removably support one of the containers in a substantially upright fashion. The holding cells can be configured to hold the containers at an average density, for example, of between about 2-8 containers per cm2, or higher. In one embodiment, the containers are disposed in the rack at an average density of between about 3-6 containers per cm2; and preferably between about 4-5 containers per cm2. Multiple racks (e.g., 2, 3, 4, 5, or more) can be arranged in tandem for use in an xe2x80x9cassembly linexe2x80x9d type fashion.
A plurality of different reagents can be disposed in the dispensers. In one embodiment, each dispenser contains a reagent that is unique to the array.
Beads can be employed to carry the different reagents. One embodiment of the invention provides a plurality of bead groups, or xe2x80x9clots,xe2x80x9d with each lot being comprised of substantially similar beads carrying a respective one of the different reagents. The beads can be relatively large, e.g., about 1-5 mm in diameter; or the beads can be relatively small, e.g., each having a diameter of less than about a millimeter. In one preferred embodiment, each bead has a diameter of between about 275-325 xcexcm; and preferably about 300 xcexcm.
In one embodiment, a plurality of reagent-carrying beads are held in sealed ampules. In an exemplary arrangement, the ampules are dimensioned to move downward through a dispenser passageway under the force of gravity, in a substantially single-file fashion. Preferably, all of the beads in any given ampule carry the same, or a substantially similar, kind of reagent. Further in this embodiment, each passageway of the dispenser array is loaded with a plurality of such ampules.
One embodiment of the invention provides a detection assembly adapted to detect the passage of reagent dispensed from any one of the dispensers in the array. To this end, the detection assembly is provided with a field of view extending between the dispenser outlet regions and the second support.
According to one particular embodiment, the detection assembly includes a radiation emitter, such as a diode laser, and a radiation sensor. In an exemplary arrangement, the radiation emitter is (a) mounted on the first support at a region along one side of the second support, and (b) configured to project a substantially linear radiation beam along a pathway that passes over the fixed target region of the first support. The radiation sensor can be (a) mounted on the first support at a region along an opposing side of the second support, and (b) disposed within the radiation-beam pathway.
In one embodiment, each gate mechanism of the array is subject to a biasing force that normally urges it to the closed position, thereby preventing the passage of reagent through a respective outlet region. A release mechanism, adapted for positioning near any one of the gate mechanisms, is operable to apply a secondary force of a magnitude and direction effective to override the normal biasing force so that the gate mechanism assumes the opened condition.
In one particular embodiment, each gate mechanism includes a magnetic pinch valve having first and second permanent magnets that are pivotally mounted in facing relation at a respective outlet region. The magnets have lower, confronting north and south pole regions, respectively, that are normally urged toward one another by magnetic forces so as to pivot the magnets to the closed condition. Further in this embodiment, the release mechanism can be an electromagnet operable to generate a magnetic force having south and north pole portions disposed to attract the north and south pole lower regions of the first and second pivotal magnets, respectively, so that they swing away from one another (i.e., to an open condition).
In another particular embodiment, each gate mechanism is a resiliently deflectable lever having a protrusion normally extending into a respective outlet region. Further in this embodiment, the release mechanism is a rod adapted for reciprocal linear motion between a retracted position and an extended position. Upon movement toward the extended position, the rod can mechanically engage and deflect the lever, so that the protrusion is at least partially withdrawn from the outlet region (i.e., to an open condition).
The system of the invention can further include a guide or funnel member located over the fixed target region of the first support, between the dispenser array and the second support. In a preferred embodiment, the guide member is disposed for movement with the first support to a position under any selected dispenser. The guide member is configured to channel reagent dispensed from such dispenser to a selected site on the holding area of the second support.
In one particular embodiment, the guide member includes (i) an upper opening, or inlet, that is alignable with any one of the outlet regions for receiving reagent dispensed therefrom, and (ii) a lower opening, or outlet, through which dispensed reagent may egress in route to the holding area. Preferably, the upper opening is larger than the lower opening. A conical portion can be provided between the upper and lower openings.
In another of its aspects, the present invention provides a reagent dispenser assembly.
According to one preferred embodiment, the reagent dispenser assembly includes a container adapted to receive a reagent and a gate mechanism located at a lower outlet region of the container. The gate mechanism is provided with first and second permanent magnets pivotally mounted in facing relation at the lower outlet region. The pivotal magnets have lower, confronting north and south pole regions, respectively, that are normally urged toward one another by magnetic forces so as to swing them to a closed condition whereat the egression of reagent from the container is substantially blocked.
In one embodiment, an electromagnet is disposed below the gate mechanism. In this embodiment, the electromagnet is operable to generate a magnetic force having south and north pole portions disposed to attract the north and south pole lower regions of the first and second magnets, respectively, so that these regions swing away from one another to an opened condition. In this opened condition, the egression of reagent from the container is permitted.
Another embodiment provides a rack holding a plurality of the containers at respective locations defining an array. A first movable support is disposed below the rack, upon which the electromagnetic can be mounted.
A second movable support can be mounted on the first movable support, under the electromagnet. In this embodiment, the second movable support is configured to receive and hold a multi-well plate for receiving reagents dispensed from the containers.
Still a further aspect of the present invention provides a method for loading a plurality of receptacles with one or more reagents.
According to one embodiment, the method includes the steps of (i) placing the receptacles on a support under an addressable array of reagent dispensers;
(ii) selecting a dispenser equipped to dispense a desired reagent, and a receptacle for receiving the desired reagent;
(iii) simultaneously (a) positioning a fixed target region of the support at a location under the selected dispenser, and (b) positioning the selected receptacle at a location directly over the fixed target region of the support;
(iv) dispensing the desired reagent from the selected dispenser into the selected receptacle;
(v) detecting the desired reagent as it is dispensed from the selected dispenser; and
(vi) repeating steps (ii)-(v) so that reagent is dispensed from at least one other dispenser into at least one other receptacle.
In one embodiment, each of the receptacles is a well of a multi-well tray.
In another embodiment, each of the dispensers is equipped to dispense an analyte-specific reagent that is unique to the array.
In a further embodiment, at least 100 different analyte-specific reagents are dispensed from respective dispensers into respective receptacles. Other embodiments contemplate the dispensing of at least 500, 1,000, and 10,000, different reagents.
These and other features and advantages of the present invention will become clear from the following description.